chr2-178731827-T-C

Variant names:

• chr2-178731827-T-C
• rs72648942
• NM_001267550.2:c.17048A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.17048A>G​(p.Tyr5683Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00672 in 1,613,858 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y5683D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0047 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0069 (42 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:25
• Conservation: PhyloP100: 5.16
• Publications: 15 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007775426).
• BP6: Variant 2-178731827-T-C is Benign according to our data. Variant chr2-178731827-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46621.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00469 (714/152314) while in subpopulation NFE AF = 0.00747 (508/68024). AF 95% confidence interval is 0.00693. There are 3 homozygotes in GnomAd4. There are 339 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.17048A>G	p.Tyr5683Cys	missense	Exon 58 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.16097A>G	p.Tyr5366Cys	missense	Exon 56 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.13316A>G	p.Tyr4439Cys	missense	Exon 55 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.17048A>G	p.Tyr5683Cys	missense	Exon 58 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.17048A>G	p.Tyr5683Cys	missense	Exon 58 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.16772A>G	p.Tyr5591Cys	missense	Exon 56 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00469 AC: 714 AN: 152196 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00747

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00559 AC: 1391 AN: 248668 AF XY: 0.00575

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00353

Gnomad NFE exome AF: 0.00816

Gnomad OTH exome AF: 0.00580

GnomAD4 exome AF: 0.00693 AC: 10125 AN: 1461544 Hom.: 42 Cov.: 36 AF XY: 0.00700 AC XY: 5092 AN XY: 727052

African (AFR) AF: 0.00128 AC: 43 AN: 33470

American (AMR) AF: 0.00210 AC: 94 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00961 AC: 251 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.00639 AC: 551 AN: 86258

European-Finnish (FIN) AF: 0.00397 AC: 212 AN: 53402

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.00774 AC: 8601 AN: 1111744

Other (OTH) AF: 0.00588 AC: 355 AN: 60362

GnomAD4 genome AF: 0.00469 AC: 714 AN: 152314 Hom.: 3 Cov.: 33 AF XY: 0.00455 AC XY: 339 AN XY: 74482

African (AFR) AF: 0.00130 AC: 54 AN: 41576

American (AMR) AF: 0.00327 AC: 50 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4830

European-Finnish (FIN) AF: 0.00499 AC: 53 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00747 AC: 508 AN: 68024

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00693 Hom.: 10

Bravo AF: 0.00471

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00225 AC: 9

ESP6500EA AF: 0.00719 AC: 60

ExAC AF: 0.00585 AC: 707

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00644

EpiControl AF: 0.00688

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	7	not provided (7)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Brugada syndrome (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Benign	0.35
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.70	T
PhyloP100		5.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.42
Sift	Benign	0.11	T
Polyphen		0.035	B
Vest4		0.36
MVP		0.20
MPC		0.11
ClinPred		0.052	T
GERP RS		3.8
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs72648942; hg19: chr2-179596554; COSMIC: COSV105213885; COSMIC: COSV105213885;